Andrew S. Paluch

A method for computing the solubility limit of solids: application to sodium chloride in water and alcohols.

We present an adaptable method to compute the solubility limit of solids by molecular simulation, which avoids the difficulty of reference state calculations. In this way, the method is highly adaptable to molecules of complex topology. Results are shown for solubility calculations of sodium chloride in water and light alcohols at atmospheric conditions. The pseudosupercritical path integration method is used to calculate the free energy of the solid and gives results that are in good agreement with previous studies that reference the Einstein crystal. For the solution phase calculations, the self-adaptive Wang-Landau transition-matrix Monte Carlo method is used within the context of an expanded isothermal-isobaric ensemble. The method shows rapid convergence properties and the uncertainty in the calculated chemical potential was 1% or less for all cases. The present study underpredicts the solubility limit of sodium chloride in water, suggesting a shortcoming of the molecular models. Importantly, the proper trend for the chemical potential in various solvents was captured, suggesting that relative solubilities can be computed by the method.

Small Molecule Solvation Free Energy: Enhanced Conformational Sampling Using Expanded Ensemble Molecular Dynamics Simulation.

We present an efficient expanded ensemble molecular dynamics method to calculate the solvation free energy (or residual chemical potential) of small molecules with complex topologies. The methodology is validated by computing the solvation free energy of ibuprofen in water, methanol, and ethanol at 300 K and 1 bar and comparing to reference simulation results using Bennetts acceptance ratio method. Difficulties with ibuprofen using conventional molecular dynamics methods stem from an inadequate sampling of the carboxylic acid functional group, which, for the present study, is subject to free energy barriers of rotation of 14-20 kBT. While several advances have been made to overcome such weaknesses, we demonstrate how this shortcoming is easily overcome by using an expanded ensemble methodology to facilitate conformational sampling. Not only does the method enhance conformational sampling but it also boosts the rate of exploration of the configurational phase space and requires only a single simulation to calculate the solvation free energy. Agreement between the expanded ensemble and the reference calculations is good for all three solvents, with the reported uncertainties of the expanded ensemble being comparable to the uncertainties of the reference calculations, while requiring less simulation time; the reduced simulation time demonstrates the improved performance gained from the expanded ensemble method.

Efficient Solvation Free Energy Calculations of Amino Acid Analogs by Expanded Ensemble Molecular Simulation.

We present an efficient, automated expanded ensemble method to calculate the residual chemical potential or solvation free energy by molecular dynamics simulation. The methodology is validated by computing the residual chemical potential of 13 amino acid analogs in water at 300 K and 1 bar and comparing to reference simulation data. Overall agreement is good, with the methodology of the present study reaching limiting precisions of less than 0.1 kBT in half of the total simulation time of the reference simulation study which utilized Bennetts acceptance ratio method. The apparent difference in the efficiencies is a result of the inherent advantages of the expanded ensemble method, which creates an improved decorrelation of simulation data and improves the sampling of the important regions of the configurational phase space of each subensemble. The present adaptation utilizes histograms of proposed transition energies collected throughout the entire simulation, to make extremely precise calculations of the relative free energy between neighboring subensembles.

Predicting the excess solubility of acetanilide, acetaminophen, phenacetin, benzocaine, and caffeine in binary water/ethanol mixtures via molecular simulation

We present a general framework to predict the excess solubility of small molecular solids (such as pharmaceutical solids) in binary solvents via molecular simulation free energy calculations at infinite dilution with conventional molecular models. The present study used molecular dynamics with the General AMBER Force Field to predict the excess solubility of acetanilide, acetaminophen, phenacetin, benzocaine, and caffeine in binary water/ethanol solvents. The simulations are able to predict the existence of solubility enhancement and the results are in good agreement with available experimental data. The accuracy of the predictions in addition to the generality of the method suggests that molecular simulations may be a valuable design tool for solvent selection in drug development processes.

Using MD Simulations To Calculate How Solvents Modulate Solubility

Here, our interest is in predicting solubility in general, and we focus particularly on predicting how the solubility of particular solutes is modulated by the solvent environment. Solubility in general is extremely important, both for theoretical reasons - it provides an important probe of the balance between solute-solute and solute-solvent interactions - and for more practical reasons, such as how to control the solubility of a given solute via modulation of its environment, as in process chemistry and separations. Here, we study how the change of solvent affects the solubility of a given compound. That is, we calculate relative solubilities. We use MD simulations to calculate relative solubility and compare our calculated values with experiment as well as with results from several other methods, SMD and UNIFAC, the latter of which is commonly used in chemical engineering design. We find that straightforward solubility calculations based on molecular simulations using a general small-molecule force field outperform SMD and UNIFAC both in terms of accuracy and coverage of the relevant chemical space.

Cassandra: An open source Monte Carlo package for molecular simulation

Cassandra is an open source atomistic Monte Carlo software package that is effective in simulating the thermodynamic properties of fluids and solids. The different features and algorithms used in Cassandra are described, along with implementation details and theoretical underpinnings to various methods used. Benchmark and example calculations are shown, and information on how users can obtain the package and contribute to it are provided.

Microscopic Structure and Solubility Predictions of Multifunctional Solids in Supercritical Carbon Dioxide: A Molecular Simulation Study

Molecular dynamics simulations were employed to both estimate the solubility of nonelectrolyte solids, such as acetanilide, acetaminophen, phenacetin, methylparaben, and lidocaine, in supercritical carbon dioxide and understand the underlying molecular-level driving forces. The solubility calculations involve the estimation of the solutes limiting activity coefficient, which may be computed using conventional staged free-energy calculations. For the case of lidocaine, wherein the infinite dilution approximation is not appropriate, we demonstrate how the activity coefficient at finite concentrations may be estimated without additional effort using the dilute solution approximation and how this may be used to further understand the solvation process. Combining with experimental pure-solid properties, namely, the normal melting point and enthalpy of fusion, solubilities were estimated. The results are in good quantitative agreement with available experimental data, suggesting that molecular simulations may be a powerful tool for understanding supercritical processes and the design of carbon dioxide-philic molecular systems. Structural analyses were performed to shed light on the microscopic details of the solvation of different functional groups by carbon dioxide and the observed solubility trends.

Combining MOSCED with molecular simulation free energy calculations or electronic structure calculations to develop an efficient tool for solvent formulation and selection

Solubility parameter based methods have long been a valuable tool for solvent formulation and selection. Of these methods, the MOdified Separation of Cohesive Energy Density (MOSCED) has recently been shown to correlate well the equilibrium solubility of multifunctional non-electrolyte solids. However, before it can be applied to a novel solute, a limited amount of reference solubility data is required to regress the necessary MOSCED parameters. Here we demonstrate for the solutes methylparaben, ethylparaben, propylparaben, butylparaben, lidocaine and ephedrine how conventional molecular simulation free energy calculations or electronic structure calculations in a continuum solvent, here the SMD or SM8 solvation model, can instead be used to generate the necessary reference data, resulting in a predictive flavor of MOSCED. Adopting the melting point temperature and enthalpy of fusion of these compounds from experiment, we are able to predict equilibrium solubilities. We find the method is able to well correlate the (mole fraction) equilibrium solubility in non-aqueous solvents over four orders of magnitude with good quantitative agreement.

Understanding the Solubility of Acetaminophen in 1-n-Alkyl-3-methylimidazolium-Based Ionic Liquids Using Molecular Simulation

During the manufacturing of pharmaceutical compounds, solvent mixtures are commonly used, where the addition of a cosolvent allows for the tuning of the intermolecular interactions present in the system. Here we demonstrate how a similar effect can be accomplished using a room temperature ionic liquid. The pharmaceutical compound acetaminophen is studied in 21 common ionic liquids composed of a 1-n-alkyl-3-methylimidazolium cation with 1 of 7 anions. Using the acetate anion, we predict a large enhancement in solubility of acetaminophen relative to water. We show how this is caused by a synergistic effect of favorable interactions between the ionic liquid and the phenyl, hydroxyl and amide groups of acetaminophen, demonstrating how the ionic liquid cation and anion may be chosen to preferentially solvate different functional groups of complex pharmaceutical compounds. Additionally, while the use of charge scaling in ionic liquid force fields has previously been found to have a minute effect on ionic liquid structural properties, we find it appreciably affects the computed solvation free energy of acetaminophen, which in turn affects the predicted solubility.

Predicting the equilibrium solubility of solid polycyclic aromatic hydrocarbons and dibenzothiophene using a combination of MOSCED plus molecular simulation or electronic structure calculations

ABSTRACT Methods to predict the equilibrium solubility of non-electrolyte solids are important for the design of novel separation processes. Here we demonstrate how conventional molecular simulation free energy calculations or electronic structure calculations in a continuum solvent, here SMD or SM8, can be used to predict parameters for the MOdified Separation of Cohesive Energy Density (MOSCED) method. The method is applied to the solutes naphthalene, anthracene, phenanthrene, pyrene and dibenzothiophene, compounds of interested to the petroleum industry and for environmental remediation. Adopting the melting point temperature and enthalpy of fusion of these compounds from experiment, we are able to predict equilibrium solubilities. Comparing to a total of 422 non-aqueous and 193 aqueous experimental solubilities, we find the proposed method is able to well correlate the data. The use of MOSCED is additionally advantageous as it is a solubility parameter-based method useful for intuitive solvent selection and formulation.